FtsZ is a well-conserved protein that is essential for the viability of a wide range of bacteria. During cell division, FtsZ undergoes guanosine 5′-triphosphate (GTP)-dependent polymerization to form the Z ring at the mid-cell. FtsZ recruits other proteins that together drive cell division and the formation of new cell poles.
FtsZ is a distant structural and functional homologue of mammalian β-tubulin, the target of the taxane class of anticancer drugs.
International Publication Nos. WO 2007/107758, WO2009/037485 and WO2009/040507 disclose classes of Applicant's compounds that demonstrate antibacterial activity. Without being bound by theory, the present inventors believe that the antibacterial activity of the compounds in those classes is a consequence of binding to FtsZ.
The present inventors have now identified a novel class of compounds with antibacterial activity and further which demonstrate one or more advantageous properties as pharmaceuticals for use in the treatment of bacterial infections such as staphylococcal infections, for example, bacterial infections caused by drug sensitive or resistant staphylococci including but not limited to S. aureus, S. epidermidis, S. haemolyticus, S. hominis, S. lugdunensis, S. saprophyticus and S. warneri. The compounds also include a core modification with demonstrated improved pharmacokinetic properties and which also allows for the introduction of, for example, solubilising moieties, prodrug moieties and the like in addition to a chiral centre and accordingly, enantiomeric R and S forms or a mixture thereof. In addition, the class also includes compounds which have improved activities against spontaneous first step mutations.